0:14Skip to 0 minutes and 14 secondsHello. In this short video, we'll bring the story of flu up to date, looking at the pandemics we've had since 1918. You may have seen the video in which we looked at how the H1N1 pandemic flu of 1918, the so-called Spanish flu, left descendants that returned each year as seasonal flu. In one year, 1947, the seasonal flu was particularly severe. Occasionally this will happen. Usually because antigenic drift, the capacity of the flu virus to evolve away from the host immune system, had been particularly strong in that year. One other bad year of seasonal flu in the UK was 1999 to 2000. In years of this kind, it isn't unusual for half a million people to die worldwide.

0:58Skip to 0 minutes and 58 secondsMore recently, the winter of 2014 -2015 was predicted to be a severe year in the northern hemisphere but, fortunately, things turned out to be milder than expected. The important point to grasp for the moment is that even seasonal flus can be very severe on occasions. But the difference between a seasonal flu and a pandemic flu isn't just one of severity. To illustrate this, we need to go back to 1957. In that year, a completely new variant of flu appeared, causing the second pandemic of the 20th century. Its origins seem to be in East Asia, and it was, therefore, nicknamed Asian flu. Its subtype was not H1N1, like the Spanish flu, but H2N2.

1:45Skip to 1 minute and 45 secondsThis change led to the introduction of a new phrase to describe how flu evolves. This is antigenic shift. Whereas antigenic drift refers to the relatively slow accumulation of changes in the virus, as a result of evolution to avoid the host immune system, antigenic shift implies the replacement of one predominant strain of flu with a completely new one. And that is, indeed, what happened. After the first surge of the H2N2 pandemic, the subsequent years saw H2N2 returning as a seasonal flu. H1N1, the seasonal descendant of the 1918 Spanish flu pandemic, appeared to have gone extinct. In the light of these events, the World Health Organization developed a definition of pandemic flu which required antigenic shift.

2:34Skip to 2 minutes and 34 secondsNow, things weren't actually quite that simple, but that fact wasn't realised until a few years later. In fact, we now know that the H2N2 pandemic strain was actually partly descended from the previous seasonal H1N1 as a result of our hybridisation process with a bird flu strain. The mechanism by which these hybridisation events occur is called reassortment. And this is another of the crucial concepts for understanding of flu biology. We'll look at the structure of the flu virus in a related video, and see in some detail exactly how reassortment works, and consider the circumstances in which it might happen.

3:15Skip to 3 minutes and 15 secondsThe second reason why it's premature to believe that the Spanish flu, or more correctly, its distant seasonal descendants was extinct, is also something we'll come to shortly. For another 10 years after 1957, the descendants of the Asian flu strain, H2N2, returned as a seasonal flu, antigenically drifting each year, always trying to stay just one step ahead of the host's immune system. Then in 1968, there was a third pandemic. The antigenic shift on this occasion was the appearance of H3N2. Since the first cases were detected in Hong Kong that year, the 1968 pandemic was referred to as Hong Kong flu. As the antigenic shift theory predicted, H2N2 disappeared. And from 1969 onwards, H3N2 occupied the seasonal flu slot.

4:07Skip to 4 minutes and 7 secondsIt's generally believed now that the H3N2 strain was also a reassortment, this time between the H2N2 seasonal virus, and again, a bird flu virus. Neither the 1957 Asian flu pandemic nor the 1968 Hong Kong flu pandemic were anywhere as severe as 1918's Spanish flu. The death toll around the world in 1957 was just over 2 million, and it was slightly less than that in the H3N2 pandemic of 1968. These figures are, of course, rather worse than even the most virulent seasonal flu years. But, nevertheless, the world was spared the kind of massive calamity that had occurred in 1918.

4:50Skip to 4 minutes and 50 secondsThe occurrence of two flu pandemics inside barely more than a decade was really a warning development, because it showed that flu pandemics need not necessarily be rare events. And it lent weight to the suggestion that they are rather part of influenza's normal ecology, and that we should expect more of them in the future. And, indeed, it was less than a decade later, in 1977, that yet another subtype surfaced. This one, however, was altogether more mysterious. And its origins are still disputed even today. Russian flu, as it was called, was first detected in 1977, in the Soviet Union. It soon spread around the world, but was considerably less severe than any of the previous pandemics.

5:36Skip to 5 minutes and 36 secondsAnd, in fact, it was barely worse than a bad seasonal flu year. The subtype of Russian flu was H1N1, which is, of course, the same as Spanish flu, and the seasonal flus that had circulated from 1918 up to 1957. But when the molecular analysis came in a few years later, it revealed the astonishing fact that this new strain, Russian flu, was a descendant of Spanish flu, and what's more, it looked exactly like the pre-1957 seasonal H1N1 strain. This presented some difficulties for the by-now accepted antigenic shift theory. Long extinct strains of flu were simply not expected just to come back from the dead after 20 years as some kind of viral zombie.

6:22Skip to 6 minutes and 22 secondsSo, soon a consensus of opinion developed that Russian flu must be a laboratory escapee - a strain of flu kept in the freezer since the 1950s, and somehow getting back out into the world 20 years later to cause the Russian flu outbreak of 1977. We'll probably never know for sure, but that looks like the only way to explain the virtual identity between Russian flu of 1977 and the last seasonal descendant of Spanish flu in 1957. Whatever the origins of Russian flu, it didn't succeed in driving Hong Kong flu off the scene. After 1977, there were, therefore, two seasonal flu strains circulating every winter.

7:05Skip to 7 minutes and 5 secondsA seasonal descendant of Russian flu, and a seasonal descendant of Hong Kong flu, which stubbornly defied the antigenic shift theory, and kept circulating. Some years, H1N1 would be the predominant form, and other years, H3N2, and often both. And this proved that there was no particular reason why human populations couldn't support more than one strain of seasonal flu. After this turbulent period in the third quarter of the 20th century, things settled down. We had to wait until the 21st century for our next flu pandemic. In 2009, a new pandemic strain emerged, apparently from Mexico. Although, as is often the case with pandemics, its exact origins were disputed. Nobody, after all, particularly likes to have a horrible disease named after them.

7:54Skip to 7 minutes and 54 secondsMexican flu was also an H1N1, but of a variety quite different to Spanish flu and its Russian flu descendants. 2009's version of H1N1 looked more like the kind of flu already observed in pigs, hence its other nickname, swine flu. Whereas the 1957 and 1968 pandemics had been produced by reassortments between human seasonal strains and bird flu, the 2009 pandemic strain was a reassortment of two pig flu strains, neither of which had previously shown any potential to spread within humans. Generally, flu viruses that come straight from other species into humans are very severe. For instance, every year, several poultry farmers, mostly in the poorer parts of the world, catch bird flu and the fatality rate is extremely high.

8:45Skip to 8 minutes and 45 secondsThe prediction might have been that a swine flu would be similarly virulent in humans. However, we were lucky in 2009, much as we had been in 1957 and 1968, and the pandemic was far less severe than any reasonable predictions might have suggested. Now, the descendants of swine flu circulate as a seasonal variant, but once again, as in 1977, H3N2 seasonal flu has refused to go quietly, and continues to co-circulate. The reason why H3N2 is so persistent in human populations, having survived two potential antigenic shift events, is still unclear. In 2009, it was Russian flu's descendants that were the loser. By 2011, hardly any cases of H1N1 descended from Russian flu had been recorded.

9:36Skip to 9 minutes and 36 secondsSpanish flu's resuscitation as Russian flu had, therefore, come to an end after 34 years of seasonal circulation. As I record this, in late 2015, the world of influenza has settled down again. The aftershocks of the 2009 pandemic have faded, and we're now in what we would call a normal situation, with H1N1 and H3N2 circulating as seasonal flus. This was the situation before 2009, but the difference now is that the seasonal H1N1 is a descendant of swine flu, whereas our previous seasonal H1N1 was a descendant of Russian flu. Nevertheless, if we've learned one thing from our experience of influenza in the last century, it must be that we cannot predict the time, origin, or severity of the next pandemic.

Pandemics

1918 was the worst year for pandemic influenza, but unfortunately it wasn’t our last. In 1957, 1968 and 2009, there were other flu pandemics which together killed around 6 million people.

As you watch the video, try to recall your own personal experiences of catching the flu. Were any of them in the pandemic years, or shortly after? Even if you missed the pandemic, you would likely have little immunity to its immediate seasonal flu descendents.

In the next step, we’ll be asking you to share the stories of your own encounters with influenza virus.

In 1977 there was another event, the appearance of Russian Flu, which is not officially classified by the World Health Organization (WHO) as a pandemic, although it is commonly referred to as such by virologists. The reason that the WHO did not officially regard the 1977 Russian Flu as a pandemic flu is that it looked very much like a return of the seasonal flu of the 1950s. Just as we’ll probably never know the origins of Spanish Flu, we may never get to the bottom of the mystery of where Russian Flu came from. It is likely, however, that it was a strain of seasonal flu from the 1950s that had been kept in a laboratory freezer and was accidentally released.

One fascinating new development in flu research in the last few years has been the theory of the “missing pandemic”. Detailed studies of the evolution of influenza virus - a field known as molecular phylogenetics - have raised the possibility that the seasonal flu circulating from the first isolation of influenza virus in the laboratory in 1933 to the Asian Flu pandemic of 1957, was not a direct descendant of the Spanish Flu. Since Spanish Flu was of subtype H1N1, and the first seasonal flu viruses to be isolated were also H1N1, it had always seemed reasonable to conclude that this was the case.

However, some molecular phylogeneticists have calculated that the amount of evolutionary difference between the first 1933 isolate and the 1918 Spanish Flu samples dug up from the Alaskan graveyard is too great to have accumulated via antigenic drift in just 15 years from 1918 to 1933. One way to account for this discrepancy is to hypothesise that there may have been another H1N1 influenza pandemic at some point during the 1920s - this would have been the true ancestor of the later H1N1 seasonal flu strains, and Spanish Flu would be the ancestor of modern swine flu. This theory helps to explain the findings of the molecular phylogeneticists, but to be accepted it requires identification of the “missing pandemic” in the clinical records of the 1920s. So far that has not been done. The links below provide some further reading.